期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 3, 期 2, 页码 112-117出版社
AMER CHEMICAL SOC
DOI: 10.1021/ml200244k
关键词
diversity-oriented synthesis; malaria; macrocycle; high-throughput screening phenotypic screen; infectious disease; molecular libraries probe production centers; stereochemical structure-activity relationships
资金
- NIH-MLPCN [1 U54 HG005032-1, 5 U54MH08468-1]
- NIGMS (Broad Institute CMLD) [50 GM069721]
- NIH [R01 AI079709]
- Genzyme
Here, we describe the discovery of a novel antimalarial agent using phenotypic screening of Plasmodium falciparum asexual blood-stage parasites. Screening a novel compound collection created using diversity-oriented synthesis (DOS) led to the initial hit. Structure activity relationships guided the synthesis of compounds having improved potency and water solubility, yielding a subnanomolar inhibitor of parasite asexual blood-stage growth. Optimized compound 27 has an excellent off-target activity profile in erythrocyte lysis and HepG2 assays and is stable in human plasma. This compound is available via the molecular libraries probe production centers network (MLPCN) and is designated ML238.
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